Valérie Vilgrain1, Helena Pereira2, Eric Assenat3, Boris Guiu3, Alina Diana Ilonca4, Georges-Philippe Pageaux3, Annie Sibert5, Mohamed Bouattour5, Rachida Lebtahi5, Wassim Allaham5, Hélène Barraud6, Valérie Laurent6, Elodie Mathias6, Jean-Pierre Bronowicki6, Jean-Pierre Tasu7, Rémy Perdrisot7, Christine Silvain7, René Gerolami8, Olivier Mundler9, Jean-Francois Seitz8, Vincent Vidal9, Christophe Aubé10, Frédéric Oberti10, Olivier Couturier10, Isabelle Brenot-Rossi11, Jean-Luc Raoul11, Anthony Sarran11, Charlotte Costentin12, Emmanuel Itti12, Alain Luciani13, René Adam14, Maïté Lewin14, Didier Samuel14, Maxime Ronot15, Aurelia Dinut2, Laurent Castera15, Gilles Chatellier16. 1. Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris Nord Val de Seine, Hôpital Beaujon, Clichy, France; Université Paris Diderot, Sorbonne Paris Cité, Faculté de Médecine, Paris, France; INSERM U1149, Centre de Recherche de l'Inflammation (CRI), Paris, France. Electronic address: valerie.vilgrain@aphp.fr. 2. Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges-Pompidou, Unité de Recherche Clinique, Paris, France; INSERM, Centre d'Investigation Clinique 1418 (CIC1418), Paris, France. 3. Centre Hospitalier Universitaire de Montpellier, Hôpital Saint Eloi, Montpellier, France. 4. Centre Hospitalier Universitaire de Montpellier, Hôpital Gui de Chauliac, Montpellier, France. 5. Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris Nord Val de Seine, Hôpital Beaujon, Clichy, France. 6. Centre Hospitalier Universitaire de Nancy, Hôpital de Brabois, Vandoeuvre-lès-Nancy, France. 7. Centre Hospitalier Universitaire de Poitiers, Poitiers, France. 8. Assistance Publique-Hôpitaux de Marseille, Hôpital de la Timone, Marseille, France; Université Aix-Marseille, Marseille, France. 9. Assistance Publique-Hôpitaux de Marseille, Hôpital de la Timone, Marseille, France. 10. Centre Hospitalier Universitaire d'Angers, Angers, France. 11. Institut Paoli Calmettes, Marseille, France. 12. Assistance Publique-Hôpitaux de Paris, Hôpital Henri Mondor, Créteil, France. 13. Assistance Publique-Hôpitaux de Paris, Hôpital Henri Mondor, Créteil, France; Université Paris Est Créteil, Faculté de Médecine, Créteil, France; INSERM IMRB U955 Equipe 18, Créteil, France. 14. Assistance Publique-Hôpitaux de Paris, Hôpital Paul Brousse, Villejuif, France. 15. Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris Nord Val de Seine, Hôpital Beaujon, Clichy, France; Université Paris Diderot, Sorbonne Paris Cité, Faculté de Médecine, Paris, France; INSERM U1149, Centre de Recherche de l'Inflammation (CRI), Paris, France. 16. Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges-Pompidou, Unité de Recherche Clinique, Paris, France; INSERM, Centre d'Investigation Clinique 1418 (CIC1418), Paris, France; Université Paris-Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France.
Abstract
BACKGROUND:Sorafenib is the recommended treatment for patients with advanced hepatocellular carcinoma. We aimed to compare the efficacy and safety of sorafenib to that of selective internal radiotherapy (SIRT) with yttrium-90 (90Y) resin microspheres in patients with hepatocellular carcinoma. METHODS:SARAH was a multicentre, open-label, randomised, controlled, investigator-initiated, phase 3 trial done at 25 centres specialising in liver diseases in France. Patients were eligible if they were aged at least 18 years with a life expectancy greater than 3 months, had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, Child-Pugh liver function class A or B score of 7 or lower, and locally advanced hepatocellular carcinoma (Barcelona Clinic Liver Cancer [BCLC] stage C), or new hepatocellular carcinoma not eligible for surgical resection, liver transplantation, or thermal ablation after a previously cured hepatocellular carcinoma (cured by surgery or thermoablative therapy), or hepatocellular carcinoma with two unsuccessful rounds of transarterial chemoembolisation. Patients were randomly assigned (1:1) by a permutated block method with block sizes two and four to receive continuous oral sorafenib (400 mg twice daily) or SIRT with 90Y-loaded resin microspheres 2-5 weeks after randomisation. Patients were stratified according to randomising centre, ECOG performance status, previous transarterial chemoembolisation, and presence of macroscopic vascular invasion. The primary endpoint was overall survival. Analyses were done on the intention-to-treat population; safety was assessed in all patients who received at least one dose of sorafenib or underwent at least one of the SIRT work-up exams. This study has been completed and the final results are reported here. The trial is registered with ClinicalTrials.gov, number NCT01482442. FINDINGS: Between Dec 5, 2011, and March 12, 2015, 467 patients were randomly assigned; after eight patients withdrew consent, 237 were assigned to SIRT and 222 tosorafenib. In the SIRT group, 53 (22%) of 237 patients did not receive SIRT; 26 (49%) of these 53 patients were treated with sorafenib. Median follow-up was 27·9 months (IQR 21·9-33·6) in the SIRT group and 28·1 months (20·0-35·3) in the sorafenib group. Median overall survival was 8·0 months (95% CI 6·7-9·9) in the SIRT group versus 9·9 months (8·7-11·4) in the sorafenib group (hazard ratio 1·15 [95% CI 0·94-1·41] for SIRT vs sorafenib; p=0·18). In the safety population, at least one serious adverse event was reported in 174 (77%) of 226 patients in the SIRT group and in 176 (82%) of 216 in the sorafenib group. The most frequent grade 3 or worse treatment-related adverse events were fatigue (20 [9%] vs 41 [19%]), liver dysfunction (25 [11%] vs 27 [13%]), increased laboratory liver values (20 [9%] vs 16 [7%]), haematological abnormalities (23 [10%] vs 30 [14%]), diarrhoea (three [1%] vs 30 [14%]), abdominal pain (six [3%] vs 14 [6%]), increased creatinine (four [2%] vs 12 [6%]), and hand-foot skin reaction (one [<1%] vs 12 [6%]). 19 deaths in the SIRT group and 12 in the sorafenib group were deemed to be treatment related. INTERPRETATION: In patients with locally advanced or intermediate-stage hepatocellular carcinoma after unsuccessful transarterial chemoembolisation, overall survival did not significantly differ between the two groups. Quality of life and tolerance might help when choosing between the two treatments. FUNDING: Sirtex Medical Inc.
RCT Entities:
BACKGROUND:Sorafenib is the recommended treatment for patients with advanced hepatocellular carcinoma. We aimed to compare the efficacy and safety of sorafenib to that of selective internal radiotherapy (SIRT) with yttrium-90 (90Y) resin microspheres in patients with hepatocellular carcinoma. METHODS: SARAH was a multicentre, open-label, randomised, controlled, investigator-initiated, phase 3 trial done at 25 centres specialising in liver diseases in France. Patients were eligible if they were aged at least 18 years with a life expectancy greater than 3 months, had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, Child-Pugh liver function class A or B score of 7 or lower, and locally advanced hepatocellular carcinoma (Barcelona Clinic Liver Cancer [BCLC] stage C), or new hepatocellular carcinoma not eligible for surgical resection, liver transplantation, or thermal ablation after a previously cured hepatocellular carcinoma (cured by surgery or thermoablative therapy), or hepatocellular carcinoma with two unsuccessful rounds of transarterial chemoembolisation. Patients were randomly assigned (1:1) by a permutated block method with block sizes two and four to receive continuous oral sorafenib (400 mg twice daily) or SIRT with 90Y-loaded resin microspheres 2-5 weeks after randomisation. Patients were stratified according to randomising centre, ECOG performance status, previous transarterial chemoembolisation, and presence of macroscopic vascular invasion. The primary endpoint was overall survival. Analyses were done on the intention-to-treat population; safety was assessed in all patients who received at least one dose of sorafenib or underwent at least one of the SIRT work-up exams. This study has been completed and the final results are reported here. The trial is registered with ClinicalTrials.gov, number NCT01482442. FINDINGS: Between Dec 5, 2011, and March 12, 2015, 467 patients were randomly assigned; after eight patients withdrew consent, 237 were assigned to SIRT and 222 to sorafenib. In the SIRT group, 53 (22%) of 237 patients did not receive SIRT; 26 (49%) of these 53 patients were treated with sorafenib. Median follow-up was 27·9 months (IQR 21·9-33·6) in the SIRT group and 28·1 months (20·0-35·3) in the sorafenib group. Median overall survival was 8·0 months (95% CI 6·7-9·9) in the SIRT group versus 9·9 months (8·7-11·4) in the sorafenib group (hazard ratio 1·15 [95% CI 0·94-1·41] for SIRT vs sorafenib; p=0·18). In the safety population, at least one serious adverse event was reported in 174 (77%) of 226 patients in the SIRT group and in 176 (82%) of 216 in the sorafenib group. The most frequent grade 3 or worse treatment-related adverse events were fatigue (20 [9%] vs 41 [19%]), liver dysfunction (25 [11%] vs 27 [13%]), increased laboratory liver values (20 [9%] vs 16 [7%]), haematological abnormalities (23 [10%] vs 30 [14%]), diarrhoea (three [1%] vs 30 [14%]), abdominal pain (six [3%] vs 14 [6%]), increased creatinine (four [2%] vs 12 [6%]), and hand-foot skin reaction (one [<1%] vs 12 [6%]). 19 deaths in the SIRT group and 12 in the sorafenib group were deemed to be treatment related. INTERPRETATION: In patients with locally advanced or intermediate-stage hepatocellular carcinoma after unsuccessful transarterial chemoembolisation, overall survival did not significantly differ between the two groups. Quality of life and tolerance might help when choosing between the two treatments. FUNDING: Sirtex Medical Inc.
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